Parasitic helminths induce chronic infections in their hosts, the parasite often surviving for years without obvious rejection. With most human helminthiases there is evidence that the host develops an 'acquired immunity' over time. However, with hookworm infections, protection does not develop with age, suggesting these parasites have evolved unique mechanisms to actively evade host immune responses. Larval and adult stages of the human hookworm, Necator americanus, secrete a battery of molecules, many with immunomodulatory properties. In preliminary experiments, we report that a protein(s) from excretory/secretory (ES) products of adult N. americanus binds exclusively to natural killer (NK) cells from mice and humans. In addition, in vitro incubation of purified mouse or human NK cells with ES products stimulated the cells to produce augmented levels (4 to 24-fold) of IFN-g within 24 hours of culture. These findings have led us to postulate that N. americanus secretes a protein (NKBP) that binds to NK cells and stimulates them to produce IFN-g, possibly as a means of cross-regulating deleterious TH2 immune responses. The current proposal is designed to characterize the interactions between host leukocytes and N. americanus ES products and to establish their potential role during human hookworm infection. The following specific aims are proposed: (1) To establish the effects of NKBP binding on NK cell function, (2) To characterize NKBP and its receptor on NK cells, and (3) To determine the profile of NKBP bindingand- resulting cytokine production in patients with active hookworm infections. By identifying hookworm proteins that bind to and interfere with innate and cell-mediated host responses against the parasite, we will gain insight into the molecular mechanisms that these highly adapted pathogens use to survive. In turn these have the potential to provide novel targets for therapeutic and/or preventative strategies for infections by hookworms, as well as other types of pathogens.